Nucleic acids are the fundamental informational molecules of all living organisms. We propose to explore the three-dimensional structural details of the interactions of nucleic acids with other biologically important molecules by means of single crystal x-ray crystallography. We wish to study the structure and the non-covalent sequence specific recognition of nucleic acids by antibiotics, and anti-tumor agents, mutagens, carcinogens, peptides, cations, water and other chemical probes via a trifurcated crystallographic model system using a high resolution approach. The first branch of this plan is the crystallographic analysis of antibiotics and metabolic intermediates which contain the sequence specific portions of nucleic acids (the bases) covalently bound to possible probing groups. The second path is to crystallize short defined sequence fragments of double helical nucleic acids complexed both with cations and drugs which bind to them in a defined fashion. The third artery of investigation involves the construction of a small macromolecular crystal system which uses polybasic proteins, such as protamines, to immobilize defined sequences of double helical fragments in the solid state. By diffusion of peptides, drugs, mutagens, carcinogens and specific cations into the crystal, their interaction with the nucleic acid part of the crystal may be observed directly, with a minimum of crystallograpic overhead. These studies will provide much hard geometric data about the intimate conformational and configurational details of the sequence specific recognition of nucleic acids. Via this data, we hope to gain insight into the molecular basis of the mode of drug action and the mechanism of gene expression.